This invention relates to growth hormones and more particularly to drugs which promote growth other than the human pituitary growth hormone.
Hormones are known which stimulate growth in animals by exerting a direct effect on protein, carbohydrate and lipid metabolism and control the rate of skeletal and visceral growth. Such hormones may act on more than one species although this is not necessarily true of all such hormones. Hormones are normally obtained from the animals which produce them and may be used in different therapies to stimulate growth.
One type of hormone, a human growth hormone (HGH), sometimes referred to as a pituitary hormone, is a straight chain of 191 amino acids without carbohydrate substituents. It has a molecular weight of 21,500 daltons determined by the DISC (discontinuous) gel electrophoresis method and has an isoelectric point of 4.9. The amino acid sequence for HGH is disclosed in U.S. Pat. No. 3,853,833 to Choh Li and is incorporated herein by reference.
This hormone is obtained from the human pituitary gland by elution chromatography and has been used therapeutically to stimulate growth in children deficient in growth hormone in doses usually less than 8 milligrams per day for periods sometimes exceeding 10 years. Doses of human growth hormone of 8 milligrams per day have been known to: (1) cause impairment of glucose tolerance in humans; and (2) stimulate glucose incorporation into adopose tissue, lipids and liver provided they do not have the hormone present in them.
This human pituitary hormone has several disadvantages such as: (1) it produces resistance to insulin; (2) it is diabetogenic; (3) it increases blood glucose; (4) it stimulates the breakdown of body fat; (5) it stimulates an increase in tissue receptors for the hormones prolactin and estrogen; and (6) it induces diabetes if given in large doses for extended periods of time as indicated by reduced glucose tolerance, such periods of time and dosages are sufficiently low so as preclude the use of this hormone for certain types of therapy.
It is known from the publication of Mueller, J. F. in 1963 entitled "Parasite-Induced Weight Gain in Mice" J. Parasitol, 113:217, that infection by the plerocercoid stage of the tapeworm, Spirometra mansonoides, stimulates body growth and it is known from the publications of Garland, J. T. et al, in 1971 entitled "Induction of Sulfation Factor Activity by Infection of Hypophysectomized Rats with Spirometra mansonoides" Endocrinology, 88:924 and the publication by Steelman et al, in 1970 entitled "Growth Hormone-Like Activity in Hypophysectomized Rats Implanted with Spirometra mansonoides spargana" Proc. of the Soc. of Exp. Biol. Med., 133:269, that plerocercoid injected into rats suppresses endogenous growth hormone levels and elicits other responses indicative of functional similarities to growth hormones.
The prior art describes processes for obtaining an impure drug from the plerocercoids of tapeworms and has shown that this drug competitively inhibits human growth hormone binding to its receptors in hepatic miscrosomes from female rabbits and cross reacts with anti-human growth hormone monoclonal antibodies. For example, the publication of Phares, C. K. in 1984 entitled "A Method for Solubilization of Human Growth Hormone Analog from Plerocercoids of Spirometra mansonoides", J. Parasitol, 70:840, described obtaining this drug in impure form and showing it to be an active growth factor. The drug was obtained by solubilization of the plerocercoid membranes with a non-ionic detergent. However, the purified growth factor only had a specific activity of 50 to 80 ngE (nanograms equivalent of a human growth hormone standard)/mg of protein (nanograms of the eluant for each milligram of protein). Quite surprisingly, however, applicant has characterized the amino acid sequence of plerocercoid growth factor and it has no homology to human growth hormone or any other growth hormone despite these early indications that there would be a high level of homology.
It has been known to remove human growth hormone by receptor affinity chromatography using liver membranes prepared from late pregnant rabbits. However, it was not known that affinity chromatography would be useful in purifying the growth factor in the plerocercoid stage of Spirometra mansonoides, and given the lack of homology between the two proteins it would not be expected that pleroceroid growth factor could be purified by this method.
It is an object of the invention to provide a novel drug for the treatment of growth related disorders.
It is a further object of the invention to provide a novel method for making a drug which stimulates growth in animals.
It is a still further object of the invention to provide novel methods of treatment for growth-affected diseases.
It is a still further object of the invention to provide a novel drug and method of using it to treat isolated growth hormone deficiency (hyposomatotrophic dwarfism).
It is a still further object of the invention to provide a novel drug and method of using the drug to treat normal variant short stature.
It is a still further object of the invention to provide a novel drug and method of using the drug to treat massive and uncontrolled bleeding of stress ulcers.
It is a still further object of the invention to provide a novel protein for promoting growth which does not have diebetogenicity.
It is a still further object of the invention to provide a novel protein for promoting growth which substance may be administered in higher doses and for longer periods of time than human growth hormone.
It is a still further object of the invention to provide a novel drug and method of using the drug for gastrointestinal tract diseases.
It is a still further object of the invention to provide a novel drug and method of using the drug to stimulate body growth in animals while reducing the amount of the animal's own growth hormone developed in the animal.
It is a still further object of the invention to provide a novel drug and method of using the drug to treat anorexia nervosa.
It is a still further object of the invention to a drug and method of using the drug for the treatment of anorexia nervosa without complications of diabetes mellitus, or hormone related cancers such as mammary cancer.
It is a still further object of the invention to provide a novel drug and method of using the drug to increase the growth rate and feed conversion of livestock.
It is a still further object of the invention to provide a novel substance which is substantially identical to human growth hormone in its receptor binding and activation properties but contains certain minor differences which make it a superior drug.
It is a still further object of this invention to provide a novel drug for the prevention and treatment of mammary cancer.